Dissertation/Thesis Abstract

Catalysis of the Claisen Rearrangement by Hydrogen-Bond Donors
by Uyeda, Christopher Hiroki, Ph.D., Harvard University, 2011, 345; 3446170
Abstract (Summary)

Since its initial report nearly a century ago, the [3,3]-sigmatropic rearrangement of allyl vinyl ethers—the Claisen rearrangement—has emerged as a powerful carbon–carbon bond-forming transformation in the synthesis of structurally and stereochemically complex organic molecules. A principle feature of the Claisen rearrangement that underlies its synthetic utility is the high and predictable diastereoselectivity imparted by the pericyclic mechanism, allowing α- and β-stereogenic carbonyl compounds of either the syn or anti relative configurations to be prepared from precursors bearing the appropriate alkene geometries. Recent progress in catalytic asymmetric methodology has culminated in the first examples of highly enantioselective rearrangements of achiral substrates using Lewis acid complexes; however, limitations in the scope of these reactions persist due to challenges associated with competing background rearrangement and the strong binding affinity of the products.

Chorismate mutases accelerate the Claisen rearrangement of chorismate by over a million-fold and are proposed to achieve catalysis in large part by hydrogen-bond donation from cationic lysine and arginine residues in the active site. Consistent with this mechanism of substrate activation, we have identified monofunctional guanidinium ions bearing non-coordinating counteranions as effective catalysts for the rearrangement of a variety of substrates in non-polar organic solvents.

The development of a chiral pyrrolo-cyclohexylamine-derived guanidinium ion catalyst for the enantioselective rearrangement of O-allyl α-ketoester substrates is described in chapter two. X-ray analysis in combination with computational modeling studies has led to the identification of an intramolecular π–cation interaction between the heterocycle and guanidinium ion groups that defines the overall structure of the catalyst and minimizes the number of energetically accessible conformations.

From our catalyst optimization studies, a beneficial effect on both rate and enantioselectivity was observed of catalyst aryl substituents, which are appropriately positioned to provide π-stabilization of the cationic allyl fragment in the Claisen rearrangement transition state. The third chapter outlines our mechanistic studies of this secondary non-covalent interaction and its importance in asymmetric induction.

The final chapter describes an extension of this catalyst system to the rearrangement of O-allyl β-ketoester substrates, which provides selective access to branched allylation products with control over both relative and absolute stereochemistry. Applications to the direct preparation of contiguous quaternary stereogenic arrays in natural product structures are discussed.

Indexing (document details)
Advisor: Jacobsen, Eric
School: Harvard University
School Location: United States -- Massachusetts
Source: DAI-B 72/04, Dissertation Abstracts International
Subjects: Organic chemistry
Keywords: Asymmetric catalysis, Claisen rearrangements, Hydrogen bonding, Organocatalysis
Publication Number: 3446170
ISBN: 978-1-124-49772-3
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